B lymphocyte stimulator (BLyS) is a member of the tumor necrosis factor (“TNF”) superfamily that induces both in vivo and in vitro B cell proliferation and differentiation (Moore et al., Science, 285: 260–263 (1999)). BLyS is distinguishable from other B cell growth and differentiation factors such as IL-2, IL-4, IL-5, IL-6, IL-7, IL-13, IL-15, CD40L, or CD27L (CD70) by its monocyte-specific gene and protein expression pattern and its specific receptor distribution and biological activity on B lymphocytes. BLyS expression is not detected on natural killer (“NK”) cells, T cells or B cells, but is restricted to cells of myeloid origin. BLyS expression on resting monocytes is upregulated by interferon-gamma (IFN-gamma). The gene encoding BLyS has been mapped to chromosome 13q34.
BLyS is expressed as a 285 amino acid type II membrane-bound polypeptide and a soluble 152 amino acid polypeptide (Moore et al., 1999, supra). The membrane-bound form of BLyS has a predicted transmembrane spanning domain between amino acid residues 47 and 73. The NH2-terminus of the soluble form of BLyS begins at Ala134 of the membrane-bound form of BLyS. Both the soluble and membrane-bound forms of the protein form homotrimers. Soluble recombinant BLyS has been shown to induce in vitro proliferation of murine splenic B cells and to bind to a cell-surface receptor on these cells (Moore et al., 1999, supra). Soluble BLyS administration to mice has been shown to result in an increase in the proportion of CD45Rdull, Ly6Dbright (also known as ThB) B cells and an increase in serum IgM and IgA levels (Moore et al., 1999, supra). Thus, BLyS displays a B cell tropism in both its receptor distribution and biological activity.
Based on its expression pattern and biological activity, BLyS has been suggested to be involved in the exchange of signals between B cells and monocytes or their differentiated progeny. The restricted expression patterns of BLyS receptor and ligand suggest that BLyS may function as a regulator of T cell-independent responses in a manner analogous to that of CD40 and CD40L in T cell-dependent antigen activation.
Accordingly, molecules that specifically bind BLyS would find a variety of uses in the study of the BLyS cytokine, in the manufacture and purification of BLyS in commercial and medically pure quantities, and in the development new therapeutic or diagnostic reagents.